on 25-Jul-2021 (Sun)

Brucellosis is most commonly seen in the Mediterranean countries, the Balkans, the Persian Gulf, the Middle East, and Central and South America. 2 Since the disintegration of the former Soviet Union, the Asian continent has also emerged as a significant focus. 21

The most invasive and pathogenic type of human brucellosis is due to B. melitensis, followed by B. abortus and B. suis. The most common animal hosts for B. melitensis biovars 1 to 3 are sheep, goats, camels, and buffalo; B. abortus biovars 1 to 6 are seen mostly in bison and camels; B. suis biovars 1 to 5 are reported in pigs, reindeers, and rodents; and B. canis affects dogs.

Contaminated sheep and goat milk with B. melitensis appears to be the leading source of human brucellosis worldwide. 7,25 Other routes of transmission to humans are direct contact with infected animals or their secretions through bruises and lacerations on the skin, inhalation of infected aerosols, and conjunctival inoculation. 27

Laboratorians, in particular, are likely to acquire the microorganism through aerosols or direct contact, 5,25

In a review of 71 reported laboratory-acquired cases, the median incubation period was 8 weeks. 25 Four of six pregnant laboratorians with brucellosis aborted their fetus.

Although human-to-human transmission is quite rare, congenitally and sexually transmitted cases are reported as well. 27

Brucella is an intracellular microorganism that can survive inside the macrophages, where it has specific survival mechanisms. The bacterium is protected through immune system—evading mechanisms such as blocking macrophage apoptosis, suppressing Th1-specific immune response, and inhibiting tumor necrosis factor-α (TNF-α) production. 22

A superoxide dismutase detoxifies reactive oxygen intermediates, and urease protects B. abortus and B. suis from gastric acid as they pass through the stomach. 31–33

Brucella species taken into the body arrive at local lymph nodes either inside polymorphonuclear leukocytes and macrophages or extracellular. 31 The microorganisms reproducing intracellularly spread to the neighboring cells, local lymph nodes, or reticuloendothelial organs such as liver, spleen, and bone marrow. 34,35

Granulomas are known to be more frequent in B. abortus infections. 36 Although toxemia is commonly observed in B. melitensis, abscess formation in joints and spleen is more often related to B. suis. 37

Adaptive immune responses play a crucial role in controlling the infection. Cytokines such as interferon-γ (IFN-γ) and interleukin-2 (IL-2), secreted by CD8 + T cells in particular, are the most significant agents in preventing the progression of the disease. 38

Although the presence of specific antibodies is of utmost importance in diagnosis, they play a limited role in the immune response. 6

The immunoglobulin M (IgM) antibodies increase in the first week and the IgG antibodies in the second. 37 After 4 weeks of rising, both immuno- globulin levels decrease rapidly after a successful treatment. Furthermore, IgG levels decrease faster than IgM levels with treatment. Even after eradication of active infection, IgM antibodies can remain positive in low titers for months or even years. A high level of IgG and IgA antibodies for longer than 6 months is a sign of chronic infection or relapse. 37,41

The incubation period is usually 1 to 4 weeks, although it may extend beyond several months. Although clinical differences between species are difficult to determine, B. melitensis infections are reported to present more acutely compared with disease caused by B. abortus. 24

In addition, clinical presentation and complications of B. suis infection in humans are reported to be similar to B. melitensis or B. abortus infections. 4

The disease presents as either acute febrile illness or chronic infection. The onset of symptoms may be either abrupt or insidious, developing over several days to weeks

The most frequent complaints are arthralgia, fever, and fatigue seen in up to 75% to 100% of the cases, followed by sweating, malodorous perspiration, lack of appetite, myalgia, chills, and back pain. 7,12,43

Brucellosis was formerly named undulant fever because fever waxes and wanes in due natural course of the disease. 8

The most common clinical findings are fever and hepatomegaly in one-third to one-half of patients, followed by splenomegaly, peripheral arthritis, sacroiliitis, scrotal swelling, neck stiffness, and lymphadenopathy. 44,45

Subclassifying the patients into “acute” (<8 weeks),="" “subacute”="" (8–52="" and="" “chronic”="" (="">52 weeks) categories according to the onset of the disease appears to be imprecise. 46 However, fever seems to be more frequent when the onset of the disease is within 1 month.

Focal involvement in due course of brucellosis is seen in more than half of the patient population. 44,48

Owing to its subtle nature, the disease is one of the leading causes of fever of unknown origin 49 and is one of the reasons for febrile neutropenia in endemic areas.

A relapse in brucellosis is defined by the reappearance of clinical signs and symptoms with or without a positive culture. 7 Relapse rates are frequently around 5% to 15%, depending on the regimen used. 7,44,51,52,53 It frequently occurs within 6 months after the discontinuation of therapy and tends to be milder than the original attack. 54

Osteoarticular involvement is the most common complication seen in up to half of brucellosis cases. Sacroiliitis, spondylodiskitis, and peripheral arthritis are the common types of osteoarticular lesions. 44,48 The lumbar vertebrae are frequently affected spinal sites (Fig. 226.1), 55,56 and large joints of the lower limbs, such as hips, knees, and ankles, are the most often involved joints. 6,57

Sacroiliitis is common in younger patients (Fig. 226.2), whereas spondylitis and peripheral arthritis are common in older patients. 12,58,59

The characteristic Pedro-Pons sign (a steplike erosion at the anterosuperior portion of a vertebral body) in spondylitis is noteworthy. 64

Neurologic involvement occurs in approximately 10% of cases and is a serious complication of brucellosis. 44,65 Brucellosis comprises 0.5% of all community-acquired central nervous system (CNS) infections. 66

The disease can be classified into categories: acute meningitis or meningo- encephalitis, chronic peripheral form (radiculoneuropathy), and chronic CNS infection (meningoencephalitis, myelitis, cerebellar involvement, cranial nerve palsies). 65

Headache and fever are observed in slightly more than half of the cases as the predominant complaints, followed by sweating, weight loss, and back pain. In addition, meningeal irritation is reported only in one-third of the cases, followed by confusion, hepa- tomegaly, hypoesthesia, and splenomegaly. 65

Added to that, 1.7% of Brucella meningitis did not display CNS pleocytosis. 68 Under these circumstances the disease has a quite subtle presentation and has a predilection to present chronic courses. 66

According to a multinational study on neurobrucellosis, half of the neurobrucellosis patients present to hospitals with serious neurologic complications. Cranial nerve involvement, mostly affecting the sixth and eighth cranial nerves, complicates one-fifth of the cases. Moreover, polyneuropathy and radiculopathy, depression, paraplegia, stroke, and abscess formation are reported.

Genitourinary complications are mostly seen in men and are reported in 5% to 10% of all brucellosis patients.

Any patient with scrotal pain and swelling with coexistent arthritis and arthralgia should raise consideration for brucellar epididymo-orchitis. 51

Nephritis is mostly a complication of endo- carditis

Brucella cardiovascular involvement includes endocarditis, 75 myocarditis, 76 pericarditis, 77 endarteritis, 78 thrombophlebitis, 79 and mycotic aneurysms. 80

Human brucellosis is one of the enteric fevers where systemic symp- toms generally predominate over gastrointestinal (GI) complaints. GI involvement in a brucellosis patient should be considered if there are any related signs or symptoms, such as nausea and vomiting, diarrhea, constipation, and abdominal tenderness. 82

Hepatic involvement in brucellosis covers a wide spectrum, ranging from mild elevation of aminotransferases to manifest hepatitis, including granulomatous forms, and to liver abscesses. 88

Although B. abortus tends to establish a granulomatous form of hepatitis, B. melitensis may cause both diffuse and granulomatous lesions in the liver

Respiratory system involvement in brucellosis is reported in up to 1% of cases. 44,48 Bronchitis, pneumonia, and pleural effusion are the pre- dominating pulmonary presentations. 48,92 Granulomas and solitary nodules in the lung parenchyma, as well as abscess and cavity formation, are also noted. 93,94

Although the interrelations between the development of pneumonia and airborne transmission are unclear, one of eight laboratory workers who experienced a brucellosis outbreak in a laboratory by airborne route had pneumonia. 97

In rare instances massive bleeding 102 or capillary leak syndrome, defined as unexplained capillary hyperperme- ability, can occur. 103

A wide spectrum of laboratory abnormalities related to the hematologic system in brucellosis is reported. Anemia, leukopenia, leukocytosis, thrombocytopenia, thrombocytosis, and pancytopenia are relatively common. 6,12,44,48

Nonspecific cutaneous and mucosal lesions are reported in 2% to 6% of brucellosis cases. 44,48,105 These manifestations are due to hypersensitivity, depositing immune complexes, or direct invasion by the organism. 106

Uveitis, the most frequent eye complication, followed by optic neuritis, papilledema, keratitis, conjunctivitis, and other diverse ocular complica- tions are observed in brucellosis.

Direct invasion, septic emboli from the infected site, endocardium in particular, and formation of immune complexes are reported as the mechanisms of Brucella eye disease. 111,112

Brucellosis manifests as a chronic infection resulting in sterility and abortion. Erythritol is considered as a contributor to the pathogenesis in animals. 115 Two reasons are known to be responsible for the lesser role of Brucella infection in human abortion: (1) Human placenta does not produce erythritol 7 and (2) the presence of anti-Brucella activity in human amniotic fluid may have protective effects. 116

Brucellar disease may easily be confused with tuberculous meningitis or spondylodiskitis in nonendemic and developed countries. 56,69

Blood and bone marrow are the most suitable specimens used in the isolation of Brucella. In patients receiving antibiotics, as well as patients with a chronic form of brucellosis, bone marrow culture appears more sensitive. 121

In addition, automated culture systems have improved the speed and the efficacy of Brucella isolation, usually within 3 days. 122 Moreover, automated culture systems are much more often positive than conventional cultures for sterile body fluids including cerebrospinal fluid (CSF). 122,123

Although serum agglutination test (SAT or Wright reaction) is usually recognized as the reference technique, with a positive defined as a titer of at least 1 : 160. 119,124 It is labor intensive and time consuming. Thus rose-bengal slide agglutination test (RBT), which uses stained killed B. abortus bacterial cells, offers a simple and affordable card test. The RBT has been traditionally used as a feasible format of SAT for rapid screening in emergency departments. 125,126

The Coombs antiglobulin test is used to detect nonagglutinating antibodies against Brucella cells. Serial dilutions up to high titers may be necessary to get beyond prozones with this process. 119

Immunocapture enzyme-linked immunosorbent assay (ELISA, Brucellacapt [Vircell; Granada, Spain]) adds patient serum to a microwell, which is coated with antibodies against human IgG, IgM, and IgA. Stained killed Brucella cells are added, and agglutination is observed. This method yields results comparable to the Coombs test. 127,128

Likewise, ELISA appears to be comparable to conventional serologic tests in the diagnosis of the disease. 129 However, the CDC has warned that false-positive ELISA tests for brucellosis require that positive results should be confirmed by standard agglutination tests. 130

Negative serology does not exclude the diagnosis in brucellosis, and using more than one test is recommended in probable cases. 123,131

Of note, standard serologic testing does not detect the rare human cases of B. canis because of antigenic differences. 136

In addition, Brucella antibodies can persist long after the patient’s recovery, and thus it is not always possible to distinguish patients with active disease from those with past infection. 41,132 In these cases the IgG avidity test can be valuable because high IgG avidity would suggest immune memory, not a new-onset disease.

Antimicrobials with accumulation in phagocytes may be important for therapeutic success in brucellosis (Tab le 2 26 .1 ). 137

Monotherapy is usually not recommended and is associated with frequent therapeutic failures or relapses. 7 However, the use of doxycycline or minocycline alone for 6 to 8 weeks can be considered in the absence of focal disease and may be cost-effective in countries with limited resources. 54